Acute toxicity of folic acid in mice

The toxicity of folic acid (PGA) was studied in different inbred strains of mice. LD50 values of PGA by the i.p. route showed a unique toxicity pattern. In some strains, convulsions, ataxia and weakness were observed. Histopathological study in strains S/RVCri, BDF1, DBA/2 and DBA/2fNCri showed acute renal tubular necrosis.     

Effect ofPlasmodium berghei infection on benzoic acid metabolism in mice

Summary The metabolism of benzoic acid was studied inPlasmodium berghei infected mice both in vitro and in vivo. Results of in vitro studies showed a considerable decrease in the ability of the infected liver to detoxify benzoic acid by hippuric acid formation. The in vivo study showed that hippuric acid formation decreases with increasing parasitemia and the emergence of benzoyl-glucoronide. This new pathway stops operating with further increase in parasitemia.     

Intracellular distribution of folic acid in mouse liver

Zusammenfassung Eine bedeutende Menge der gesamten Folsäure der Mäuseleberzellen ist in den Mitochondrien vorhanden. Auch nach Inkubation des Leberhomogenats mit radioaktiver Folsäure wird der Grossteil der Radioaktivität im mitochondrialen Anteil gefunden.     

Lesions in folic acid metabolism induced by primidone

Résumé Les auteurs ont étudié le mécanisme de la toxicité de la primidone (Mysoline) chez certains microorganismes. Ces recherches montrent que le métabolisme de l'acide folique est inhibé par le primidone et cela en trois étapes: (a) la réduction de l'acide folique en acide dihydrofolique, (b) le métabolisme des ptéridines nonconjugées et (c) la phosphorylation de la thymidine.

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This work was aided by grants from the National Vitamin Foundation, National Association for Mental Health, American Cancer Society, and U.S. Public Health Service. We thank Dr.Th. Robitcher, Ayerst Laboratories, New York, for aid and gifts of primidone and Dr.E. Patterson of the American Cyanamid Co., Pearl River, New York, for the gifts of unconjugated pteridine.     

A crystalline molybdophosphoric complex of folic acid

Résumé Un nouveau produit crystallin de l'acide folique avec l'acide molybdophosphorique est décrit. Ce produit a été soumis aux examens microscopique, électrophorétique et analyse élémentaire. Ce produit provoque une leucopénie chez les rats albines, ce qui indique une ressemblance probable aux antidotes de l'acide folique. D'autre part, l'observation a montré que ce produit a un effet inhibitif sur la croissance desStreptococcus faecalis R. dans des cultures renfermant de l'acide folique à des degrés différents.     

The effect of endotoxin on membrane fatty acid composition in BCG-sensitized mice

Summary The effects of endotoxin on mouse liver phospholipid fatty acid composition have been investigated. Administration of endotoxin fromSalmonella abortus equi led to a decrease in the polyunsaturated fatty acid content of livers from mice sensitized with Bacille Calmette Guérin (GCG). The content of arachidonic acid fell significantly in both the phosphatidylcholine and phosphatidylinositol fractions whereas in the phosphatidylethanolamine fraction the linoleic acid content was significantly reduced. The polyunsaturated fatty acids were replaced by increased amounts of oleic acid and palmitic acid, leading to a reduction in the polyunsaturated to saturated fatty acid ratio.     

Acute inhalation toxicity of ammonia in rabbits]

The aggressivity of ammonia at the pulmonary alveole level (intoxications in controlled ventilation) leads to an acute pulmonary oedema and cardio-vascular disfunctioning. Bradycardia is an early symptome (2,500 X 10(-6) but the real syndrome appears at 5,000 X 10(-6). Arterial pressure variations and blood gases modifications are significant, acidosis is systematic.     

Effects of retinoic acid on embryonic development of mice in culture

Summary The effects of all-trans-retinoic acid (RA) (tretinoin) on the craniofacial development of mouse embryos were examined using whole embryo culture. In day 8 embryos cultured for 48 h, embryonic growth was inhibited concentration-dependently by all-trans-RA treatment. Most of the treated embryos exhibited hypoplasia of the primary palatal processes and a reduction in the development of the first viscreral arches. In day 10 embryos cultured for 48 h, although embryonic growth was not inhibited at any concentrations of all-trans-RA, median cleft lip (93%), hypoplasia of the primary palatal processes (37%) and limb reduction deformities (48%) occurred commonly. Furthermore, RA treatment greatly reduced the size of the secondary palatal processes. The incorporation of³H-thymidine in the treated maxillary processes was decreased to 65% of the control value at 1.0×10^–7 M alltrans-RA. These findings indicate that all-trans-RA is teratogenic in mouse whole embryo culture.     

Circadian variation of diazepam acute toxicity in mice

Summary The LD₅₀ of i.p. injected diazepam was determined every 4 h over a 24-h period in albino mice adapted to a 12-h dark/12-h light programmed illumination cycle. Results show that diazepam is more toxic during the light phase of the cycle than during the dark phase and demonstrate circadian variation in the toxicity of the compound in mice.     

Behaviour of sodium-potassium-activated adenosine triphosphatase in rat kidney tissue by folic acid

Zusammenfassung Männliche Wistarratten zeigten nach i.v. Gabe von Folsäure einen Aktivitätsabfall der Enzyme, die in den aktiven Ionentransport eingreifen: (Na⁺K⁺) ATPase (60% gegenüber Kontrollen), ICDH (56%) und MDH (48%) und a.Ptase (66%).

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With technical assistance of Mrs. I.Bieder and Miss M.Kirstein.

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With the support of the Schweiz. Nationalfonds zur Förderung der wissenschaftlichen Forschung No. 4809.     

Neutrophilic granulocytosis following lead acetate in female mice

Summary Lead induces an abrupt neutrophilic granulocytosis with the peak response detected 4 days after treatment. Using the incorporation of tritiated thymidine as an index of neutrophil production, autoradiographic analysis revealed that only about 16% of the total neutrophil increase is associated with a stimulatory effect on production. The remainder of the increase appears to be linked to the panhistotoxic action of lead, promoting migration of neutrophils from reserve sites in the wake of tissue damage.     

Administration of D-alanine did not cause increase of D-amino acid oxidase activity in mice

D-amino acid oxidase (DAAO) activity was not altered in the liver and kidney by oral administration of D-alanine to adult mice. The enzyme was apparently not induced by the enteric microflora either, since the enzyme activity in the liver and kidney of germ-free mice was not different from that of specific-pathogen-free mice. The times of appearance of DAAO activity and of free D-amino acids in the kidney were elucidated using suckling mice. DAAO activity started to increase 7 days after birth, and reached almost the adult level by 28 days. The content of free neutral D-amino acids also increased with age, in a similar fashion. A possible conclusion is that the enzyme activity normally increases during this period, to eliminate the free D-amino acids which have increased with age in the suckling mice. Consequently, the administration of D-alanine had no further effect in increasing enzyme activity.     

Protection by antioxidants against ozone toxicity in mice

Zusammenfassung 16 Antioxidantien wurden auf ihre Schutzwirkung gegen Ozontoxizität in Mäusen geprüft. AHQ, Primaquin und EMQ waren hochwirksam, BHA, NDGA und Ascarbinsäure mässig wirksam, und die übrigen zeigten keinen nennenswerten Effekt.

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We thank Dr. D.Coffin for his advice and for the gift of the exposure chambers. This work was supported by N.I.H. Grants No. C-6516 and No. FR-05526 (to the Children's Cancer Research Foundation, Inc.) and has been submitted in partial fulfillment of requirements for an MS thesis at the North Eastern University, Boston, Massachusetts (by L.Pagnotto).     

Hydroxyproline concentration in soluble and insoluble material from serum treated with trichloroacetic acid in postpartum mice

Summary The hydroxyproline concentration in both the soluble and insoluble material from trichloroacetic acid-treated serum from postpartum mice was determined. The hydroxyproline concentration in the insoluble material increased, but that in the soluble material did not increase during the uterine involuting period.     

On the mechanism of action of some 4-aminoanalogues of folic acid

Zusammenfassung Der Einfluss einiger 4-Aminoanalogen der coenzymatisch aktiven Folsäurederivate auf die Enzyme der Folsäureumwandlungen wurde verfolgt. Die stärkste Hemmung zeigen alle 4-Aminoanaloge auf die Hydrogenase der Folsäure, wobei die Hydrierung des Pyrazinringes dieselbe deutlich vermindert. Eine mässige, jedoch deutlich schwächere Hemmung von nonkompetitiver Natur wurde bei der Hydroxymethyltetrahydrofolsäuredehydrogenase, Formiminotransferase und Leukovorincyclodehydrase festgestellt. Weiter wurde die enzymatische Hydroxymethylierung von Tetrahydroaminopterin durch Serinaldolase aus der Taubenleber beobachtet.     

Ethacrynic acid hyperglycaemia in mice

Résumé L'administration de grandes doses de l'acide Ethacrynic par injection i.p. aux souris produit l'hyperglycémie. Les investigations préliminaires indiquent un rôle important pour la médulle surrénale dans la production de la réponse hyperglycémique.     

Enhanced toxicity of the immunosuppressant ovalicin upon application to the skin

Summary The non-myelotoxic immunosuppressive sesquiterpene ovalicin, of fungal origin, is much more toxic when applied to the skin of animals than when injected i.v., the LD-50 in guinea pigs being 0.2 in the first case and 7 mg/kg in the second. It elicits aphagia and adipsia. It is assumed that ovalicin effects are due to slow, tissue-specific, metabolic toxification.     

Acute toxicity of dimethylnitrosamine in the presence of inhibitors of DMN demethylase

Summary The LD₅₀ of DMN was determined in groups of mice in the presence of inhibitors of DMN demethylase. Piperonyl butoxide, dibutylnitrosamine and nitrososarcosine had no effect on the acute toxicity of DMN. Diethylnitrosamine and DMN were markedly synergistic. All mice treated with 100 mg/kg diethylnitrosamine and 10.7 mg/kg DMN died. These results suggest that DMN demethylase may not be involved in theaacute toxicity of DMN.We thank Dr.D. B. Couch, Mr.E. J. Greene and Dr.A. E. Munson for their technical assistance.     

Folic acid levels in blood and seminal plasma of normo- and oligospermic patients prior and following folic acid treatment

Folic acid was estimated in blood and seminal plasma of normo- and oligospermic men. Following folic acid administration (10 mg TID for 30 days), the levels in blood and semen increased. However, sperm counts, motility and DNA content of spermatozoa were not affected.     

Mutagenicity and toxicity of chloroethylene oxide and chloroacetaldehyde

Summary Exposure of severaltrp-auxotrophicEscherichia coli strains, carrying base0pair substitutions, to chloroethylene oxide or chloroacetaldehyde (two metabolites of vinyl chloride) increased the mutation frequency to tryptophan prototrophy. Strong cytotoxic and mutagenic effects were observed with 2.5 mM chloroethylene oxide, while a higher concentration of chloroacetaldehyde (100 mM) exhibited a mutagenic effect which was 400 times lower.I am grateful to Prof. G. Michel, Laboratoire de Biochimie Microbienne, and to Dr H. Bartsch, International Agency for Research on Cancer, for the support of this work. I wish to thank Dr F. Besson-Simien and Dr A. Barbin for their collaboration.